The lipopeptide Pam3CSK4 inhibits Rift Valley fever virus infection and protects from encephalitis.

Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam₃CSK₄ inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam₃CSK₄ blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam₃CSK₄ treatment protected animals from infection and mortality. Overall, Pam₃CSK₄ is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections. Author summary: Rift Valley fever virus (RVFV) is an emerging mosquito-borne pathogen, which has shown the potential to spread geographically, and which can cause severe disease in humans. One of the most serious complications of RVFV infection is invasion into the brain. There are no approved treatments for RVFV infection, or any other bunyavirus that infects the brain. We found that the classically antiviral interferon pathway was not protective in neurons. This led us to screen for new antivirals, and we identified Pam₃CSK₄, which inhibited RVFV and related bunyaviruses, but not vesicular stomatitis virus. We found that the antiviral activity of Pam₃CSK₄ was separate from its previously characterized activity as a TLR2 agonist. Instead, Pam₃CSK₄ blocked RVFV entry at the step of viral membrane fusion. Importantly, we found that Pam₃CSK₄ prevented RVFV infection in the mouse brain. This work reveals that Pam₃CSK₄ prevents encephalitic bunyavirus infection in neurons, a vulnerable cell type, and future research should evaluate the therapeutic potential of Pam₃CSK₄. [ABSTRACT FROM AUTHOR]